The present invention relates to pharmaceutically useful salts forms of olanzapine, pharmaceutical compositions comprising the same and uses thereof.
Olanzapine is a pharmaceutically active compound that can be represented by formula (1).
It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water; i.e., solubility at pH 6.8=0.02 mg/ml.
The olanzapine base is known to exist in various crystalline modifications and in various hydrated forms that are generally stable at ambient conditions; see for example EP 733635 and corresponding U.S. Pat. No. 5,736,541; WO 98-11893; and EP 831098. Having so many different forms is considered to be a disadvantage as repeated production of olanzapine substance may give rise to unpredictable amounts of the respective modifications in the product, which in turn can influence the properties of the product such as in tabletting and/or releasing of the active from the tablets after ingestion.
WO 99-16313 discloses olanzapine pamoate as a pharmaceutical agent. It is a compound that is also insoluble in water and is useful particularly in intramuscular depot forms. However, like the free base, the pamoate salt exists in several forms including hydrates, solvates, and in different counter ion ratios.
WO 03-007912 discloses an amorphous lyophilized olanzapine in a reconstitutable parenteral formulation. The olanzapine is “intimately mixed” with a stabilizer and a solubilizer. The stabilizer is preferably lactose and the solubilizer includes organic acids and most preferably tartaric acid. The composition is formed by lyophilizing, i.e. a type of freeze drying, a solution of olanzapine, the stabilizer and the solubilizer to form the intimate mixture. The resulting lyophilized amorphous product can be reconstituted with parenteral diluents to make an injectable composition. Whether the tartaric acid salt of olanzapine is present in the lyophilized product is unclear.
It would thus be desirable to have a stable, solid form of olanzapine that was resistant to forming solvates. Further, it would be advantageous to have a crystalline form of olanzapine that had improved water solubility.